US6147102A - Clonidine preparations - Google Patents
Clonidine preparations Download PDFInfo
- Publication number
- US6147102A US6147102A US09/427,367 US42736799A US6147102A US 6147102 A US6147102 A US 6147102A US 42736799 A US42736799 A US 42736799A US 6147102 A US6147102 A US 6147102A
- Authority
- US
- United States
- Prior art keywords
- clonidine
- accordance
- aqueous gel
- gel
- topical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to the relief of sympathetically maintained peripheral neuropathic pain syndromes, and in particular, to the use of gel compositions containing clonidine.
- Sympathetically maintained peripheral neuropathic pain syndromes of acute or chronic origin can encompass painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), complex regional pain syndrome(CRPS) and like chronic non-malignant neuropathic pain syndromes.
- Patients with sympathetically maintained peripheral neuropathic pain syndromes typically have stimulus-independent (ongoing) pain and stimulus-dependent pain (hyperalgesia).
- Clonidine in particular, is a potent ⁇ 2 -adrenergic partial agonist used primarily for the treatment of hypertension (Jarrott et al., "Clonidine: Understanding its disposition, sites, and mechanism of action", Clin. Exp. Pharm. Physiol., 14, 471-479 (1987)).
- This drug stimulates ⁇ 2 -adrenoceptors in the vasomotor centers, causing a reduction of sympathetic outflow from the central nervous system. Both cardiac output and peripheral resistance are reduced resulting in a decrease in blood pressure.
- Higher concentrations cause a vasoconstriction by activation of postsynaptic receptors in vascular smooth muscle.
- the significant advantages of the drug are counter balanced by certain troublesome side effects including dryness of the mouth and a discouraging dizziness. Therefore, the blood concentration of clonidine must be controlled within a narrow therapeutic window.
- Clonidine and related ⁇ 2 -adrenergic agonists have been reported to modify nociception in animal models. See Yaksh, T. L., "Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing", Pharmacol. Biochem. Behav., 22, 845-858 (1985); and Nakamura et al., "Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances", Eur. J. Pharmacol., 146, 223-228 (1988).
- Hyperalgesia is defined as a leftward shift of the stimulus-response function, such that a lowering of pain threshold or an increase in pain to suprathreshold stimuli or both is observed.
- the decrease in pain threshold to mechanical or thermal stimuli may be such that lightly stroking the skin evokes pain, a phenomenon sometimes referred to as allodynia.
- clonidine is a desirable potent analgesic drug, it has a narrow therapeutic index.
- a desirable treatment for sympathetically maintained peripheral neuropathic pain syndromes would be a topical composition of clonidine that could be spread over the entire painful area to deliver targeted high concentrations to the painful site yet affording minimum systemic concentrations.
- the present gel composition answers the need for delivering therapeutically effective amounts of clonidine directly to the affected region of patients suffering sympathetically maintained peripheral neuropathic pain syndromes while avoiding undesirable systemic effects.
- Topical aqueous gel compositions containing clonidine are suitable for relieving sympathetically maintained peripheral neuropathic pain.
- Sympathetically maintained peripheral neuropathic pain is relieved by topically applying, to the affected region of a patient suffering from such pain, a pain relieving amount of an aqueous gel comprising clonidine, and a pharmaceutically acceptable water-gelling agent.
- the aqueous gel has a physiologically tolerable pH value.
- the gels contain clonidine present in an amount in the range of about 0.01 to about 0.5 weight percent based on the weight of the gel.
- a preferred gel contains clonidine in an amount in the range of about 0.01 to about 0.075 weight percent, based on the weight of the gel.
- the gelling agent is a carbomer, a glycerin polyacrylate, or a mixture thereof.
- the gelling agent can provide moisturizing, skin-humectant benefits as well.
- a preservative, a topical anesthetic and a supplemental skin-humectant also can be present.
- the topical clonidine gels can be applied and spread over the entire affected region of a patient suffering from a sympathetically maintained peripheral neuropathic pain syndrome, such as from diabetic neuropathy, postherpetic neuralgia and like peripheral neuropathic pain syndromes.
- these topical clonidine gels are capable of delivering relatively high amounts of clonidine directly to the affected region where required while limiting the total amount of clonidine going into the general circulation to levels that avoid or at least minimize systemic adverse effects.
- FIG. 1 is a graph illustrating clonidine plasma concentrations in nanograms/milliliter following regimens of topical applications of aqueous gels containing 0.1% clonidine applied in unit doses which provide total daily dosage amounts of about 3 milligrams and about 6 milligrams of clonidine/day in accordance with the present invention.
- clonidine refers to N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine and includes the pharmaceutically acceptable salts thereof, e.g., the hydrochloride salt thereof.
- pharmaceutically acceptable means that the ingredient is not a known irritant or sensitizer of human skin and has not been prohibited or restricted from use in topical skin products by the Food and Drug Administration.
- gel refers to viscous, aqueous compositions preferably containing at least about 85 weight percent water on a total gel weight basis and a sufficient amount of pharmaceutically acceptable water-gelling agent to produce a viscoelastic composition having a thixotropic viscosity.
- Topical gels containing clonidine were prepared that provided increased pain relief for more patients suffering from sympathetically maintained peripheral neuropathic pain syndromes by delivering clonidine directly to the entire affected region employing concentrations of clonidine greater than those of prior art attempts.
- the region of pain varies with the condition treated, e.g., painful diabetic neuropathy may involve only one foot or both feet, or the feet and hands, or the feet, calves and hands. Therefore, the total dose given will vary depending on the region of involvement and the corresponding amount of gel required to cover the affected regions. If too much clonidine is applied, systemic concentrations of clonidine rise to levels appropriate for antihypertensive therapy and thus cause treatment limiting side effects. The side effects in normotensive people can include dizziness, sedation, drymouth, bradycardia, and hypotension. Therefore, the present formulations and delivery methods balance the amount applied (concentration and total amount) with the size of the region to be treated with avoidance of high systemic clonidine blood concentrations.
- Another factor is the variability of each individual's perception of pain and response to treatment. A sufficiently high dose must be available to those patients who have higher pain tolerance thresholds. These patients are not likely to respond to allowable systemic concentrations from oral or patch technology administration.
- An appropriate gel vehicle is necessary for ease of drug administration, drug solubility and stability, as well as drug concentration and pH value to provide the necessary non-ionized concentration of drug with the requisite thermodynamic activity for effective topical delivery and bioavailability.
- Clonidine is employed in a therapeutically effective amount, preferably in the form of clonidine base.
- concentration of clonidine may vary, depending on the nature and degree of the pain syndromes being treated and whether the drug is being administered for therapeutic or prophylactic purposes.
- the total daily amount of clonidine absorbed by the patient in need of treatment from doses of topically applied gel is not more than about 0.2 nanograms/milliliter, based on blood plasma concentrations to avoid undesirable systemic effects.
- the present topical clonidine gel contains at least about 0.01 weight percent clonidine, based on the total weight of the gel.
- clonidine is present in an amount in the range of about 0.01 to about 0.5 weight percent, more preferably in the range of about 0.01 to about 0.25 weight percent, and most preferably in the range of about 0.01 to about 0.075 weight percent, based on the weight of the gel.
- Pharmaceutically acceptable water-gelling agents preferably are carbomers, glyceryl polyacrylates, and combinations thereof.
- Carbomers are a series of water-gelling homopolymers of acrylic acid crosslinked with an allyl ether of pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene available in various viscosity grades sold under the trademark designation CARBOPOL® by B. F. Goodrich Company, Cleveland, OH. Particularly preferred is CARBOPOL® 980.
- Glyceryl polyacrylates are esters of glycerine and polyacrylic acid available in various viscosity grades sold as an aqueous jelly under the trademark designation, HISPAGEL, by Hispano Quimica S.
- the glyceryl polyacrylate preferably is a minor portion of the total amount of water-gelling agent used. Glyceryl polyacrylate, if present, also contributes a skin moisturizing effect.
- the water-gelling agent imparts a desirable viscous, thixotropic consistency to the topical gel when mixed with clonidine and water.
- the gel contains at least about 85 percent by weight water, more preferably 95 percent by weight water, based on the total weight of the gel.
- the amount of gelling agent can vary depending on degree of gel viscosity desired.
- the amount of water-gelling agent is in the range of about 0.1 to about 2 weight percent, more preferably of about 0.5 to about 1.5 weight percent, and most preferably not more than about 1 weight percent, based on the total weight of the gel.
- the water-gelling agent may also provide some skin-humectant benefits by maintaining moisture at the affected site, without interfering with the pain relieving efficacy of the clonidine, thereby minimizing the need for applying additional skin-moisturizing products.
- supplemental, water-soluble, skin-humectant adjuvants that have skin-moisturizing properties or anti-irritant properties also can be included, so long as they do not interfere with the pain relieving efficacy of the clonidine.
- Example skin-humectants include but are not limited to polyhydric alcohols having two to six carbon atoms per molecule, such as glycerin, sorbitol, propylene glycol, and polyglycerols having two to ten glycerin units and the like.
- the amount of skin-humectant, when present, can vary in the range of about 0.1 to about 5 weight percent, preferably of about 0.5 to about 3 weight percent, based on the total weight of gel.
- Aqueous solutions of carbomer polymers form gels when neutralized with a base.
- Water-soluble bases which have been used to promote gelling of carbomers, such as the CARBOPOL® series of polymers include, for example, inorganic bases, such as an aqueous solution of NaOH, and organic bases, such as alkylamines, dialkylamines, trialkylamines, alkanolamines, dialkanolamines, trialkanolamines having one to four carbon atoms in the alkyl or alkanol chain and the like.
- a presently preferred inorganic base is NaOH
- a preferred organic base is monoethanolamine or triethanolamine.
- the pharmaceutically effective component of the gel composition is itself acidic in aqueous solution, so some base neutralization is typically required to promote gelling of the carbomer.
- the topical clonidine gel may comprise clonidine in both the hydrochloride form and free base form.
- Preservatives may be incorporated in an amount effective for inhibiting growth of microbes, such as bacteria, yeast and molds, in the gel during storage. Any conventional preservative against microbial contamination of the product can be employed so long as it is pharmaceutically acceptable, is unreactive with clonidine, and is non-irritating or non-sensitizing to human skin.
- Preferred preservatives are antimicrobial aromatic alcohols, such as benzyl alcohol, phenoxyethanol, phenethyl alcohol, and the like, and esters of parahydroxybenzoic acid commonly referred to as paraben compounds, such as methyl, ethyl, propyl, and butyl esters of parahydroxybenzoic acid and the like and mixtures thereof, but are not limited thereto. Particularly preferred are benzyl alcohol and phenoxyethanol.
- the amount of preservative is preferably not more than about two weight percent, based on the total weight of the gel.
- a topical, preferably water-soluble, anaesthetic agent such as lidocaine and the like, can be included. If present, the amount of anaesthetic agent can vary in the range of about 0.1 to about 5 weight percent.
- the pH value of the gel can be in a physiologically tolerable range of about 4 to about 9, preferably of about 6 to about 8.5, most preferably of about 7.5 to about 8.25.
- physiologically tolerable refers to a gel medium that is non-irritating to human skin.
- any suitable method of adjusting the pH value of the aqueous gel may be used.
- sodium hydroxide (NaOH) is added as a concentrated aqueous (10 to 20 weight percent) solution to the aqueous vehicle containing the water-gelling agent to bring the final pH value to the desired level.
- NaOH sodium hydroxide
- carbomer carbomer
- the gel viscosity typically increases as the carbomer in the gel is neutralized with base, e.g., with NaOH or triethanolamine, following the recommendations of the carbomer manufacturer for dissolving and neutralizing the carbomer.
- ingredients listed above may be combined in any order and manner that produces a one-phase aqueous gel of the desired consistency and pH value with clonidine dissolved therein and substantially evenly distributed or dispersed throughout.
- One preferred method of preparing such a gel involves preparation of an aqueous solution of clonidine with a portion of the water content and then dissolving the gelling agent therein.
- the preservative and any remaining optional ingredients i.e., topical anaesthetic and skin-humectant adjuvant
- the pH of the mixture is adjusted by adding the pH adjusting agent as needed to simultaneously form a gel having the desired viscosity and pH value.
- Part A an aqueous solution of the water-gelling agent.
- Part B aqueous solution
- Part B aqueous solution
- Parts A and B are then combined, and the pH of the mixture is adjusted by adding the pH adjusting agent as needed to simultaneously form a gel having the desired viscosity and pH value.
- the clonidine, preservative and remaining optional ingredients can be included separately or together in either Part A or Part B.
- the gel is preferably packaged in any suitable container indicating use and from which it can be either extruded or dispensed, such as a squeezable tube, syringe, or the like, directly onto the affected region.
- the volume of gel so contained is conveniently and preferably selected to constitute a predetermined unit dose, such as a single daily dose, or two or more daily doses, or the like, to facilitate administration of a desired controlled dose to the painful affected region of a patient.
- the package can be initially sealed and be opened at the time of use. If more than a single dose is present, the package is preferably resealable by a suitable closure means.
- a preferred package is a container, such as a bottle and the like, fitted with a pump dispenser that delivers a metered predetermined standardized unit dose on actuation.
- Another presently preferred package is a moisture-impermeable packet containing an intended single unit dose.
- the packet can be initially sealed, and be opened at the time of use by tearing, cutting, or the like at a desired or planned location in the packet after which the packet is manually squeezed so that the contents are directly administratable as desired.
- the quantity of clonidine contained in a unit dose ranges from about 0.05 milligram (mg) to about 3.5 mg, more preferably in the range of about 0.15 to about 0.6 mg, most preferably in the range of about 0.3 to about 0.5 mg.
- Such a quantity of unit doses can be administered one to four times daily, at spaced intervals in a single day and over a period of days as needed.
- the total daily dose thus delivered can range from about 0.1 to not more than about 6 mg clonidine.
- a presently preferred administration procedure is to employ a unit dose of gel to deliver a dose of about 0.3 mg of clonidine administered one to four times daily to the affected painful region.
- the topical clonidine gel of this invention can be spread over the entire affected painful region of a patient to deliver targeted high concentrations to the painful site yet afford minimum systemic concentrations. This can be accomplished with the topical gel by varying the concentration of clonidine in the gel and by varying the number of applications of gel per day to provide therapeutically effective amounts while minimizing the possibility of systemic effects.
- the topical clonidine gel can be applied directly to the affected region preferably by applying gel and then rubbing the gel into the skin.
- Example 2 A third pharmacokinetic study described in Example 2 below, was conducted which compared topical daily doses of 3 mg and 6 mg clonidine and the mean plasma concentrations were found to be not more than about 0.2 nanograms/ml as shown in FIG. 1 and no side effects were observed.
- clonidine gel topical applications of clonidine gel have particular analgesic efficacy in two sympathetically maintained peripheral neuropathic pain syndromes: post-herpetic neuralgia and painful diabetic neuropathy. Pilot trials in patients with these pain syndromes showed that effective pain relief occurs over a daily dose range of about 2 mg to about 5 mg clonidine. Although clonidine doses above five mg per day were also found to be analgesic, there was no apparent beneficial increase in analgesia with the higher doses but the frequency and severity of clonidine related systemic adverse events increased.
- topical clonidine gel formulation containing 0.05 to 0.1 weight percent clonidine applied to the skin of the lower extremities, such as the foot or leg region from once a day up to three times per day affords systemic clonidine plasma concentrations below or at the lower limit of those required for antihypertensive therapy.
- these topical clonidine gels provide the necessary amount of on-site clonidine concentration for pain relief and allow the patient the opportunity to apply needed concentrations to large pain regions of the body, e.g., both feet in a diabetic neuropathy patient, feet, calves and hands/fingers in the diabetic patient or large areas of the chest or back in postherpetic neuralgia patients.
- a kilogram (kg) batch of gel was prepared having the following formula:
- An aqueous solution of clonidine was prepared in about 80% of the total water content with stirring agitation employing a propeller-type stirrer (Lightnin mixer) for about five minutes or until homogeneous. While maintaining a stirring vortex, the carbomer was sifted into the vortex of the aqueous clonidine solution and dissolved therein with continuous stirring agitation until a homogenous thin, cloudy liquid dispersion was obtained. The benzyl alcohol was added to the liquid dispersion and stirring agitation maintained for at least ten minutes.
- a propeller-type stirrer Lightnin mixer
- the pH of the mixture was measured and then adjusted and concurrently gelled by adding aqueous sodium hydroxide and mixed for about 15-30 minutes.
- the dispersion was stirred with a paddle stirrer (Hobart mixer). The pH and water content was adjusted as needed for the final gel product.
- the pH value may vary in the range of about 7.8 to about 8.2, and if necessary, aqueous (10%) hydrochloric acid NF can be added to adjust the pH to 8.
- a pharmacokinetic study was conducted to compare absorption and other pharmacokinetic characteristics following topical applications of daily doses of 3 mg and 6 mg of clonidine employing a topical gel containing 0.1 weight percent clonidine hydrochloride.
- the study mimicked the realistic use of topical clonidine gel by a patient with painful diabetic neuropathy of the feet and legs.
- normal (i.e., pain free) volunteer adults with no efficacy outcomes were selected who met the following inclusion criteria.
- Systolic blood pressure between 100 and 140 mm Hg; Diastolic blood pressure between 60 and 90 mm Hg; Pulse greater than 50 beats per minuter (BPM).
- Presence of altered skin integrity including but not limited to, skin wounds, skin abrasions or any disease state affecting dermal integrity or structure in designated application sites.
- the study was designed as an unblinded randomized cross-over regimen in which two dose levels of clonidine (3 mg and 6 mg per day) were compared to assess whether tissue saturation is dose related on the assumption topical clonidine forms a reservoir at non-specific binding sites within the skin.
- the regimen comprised the following six clinical study periods:
- Half of the randomized population started the treatment sequence with a 3 mg/day dose during Study Period (2) and then followed with the crossover sequence of the 6 mg/day dose during Study Period (5).
- the other half of the population started the first treatment with the 6 mg/day dose during Study Period (2) and then followed with the crossover sequence of the 3 mg/day dose during Study Period (5).
- the following protocol was employed for topical application of clonidine.
- One dose of one mg clonidine gel was topically applied to a selected area of the skin on the right lower leg three times a day for a total application of three mg clonidine/day to the same designated skin area for a period of 14 consecutive days, during either Study Period (2) or Study Period (5).
- a dose of one mg clonidine gel was applied to a selected area of the right leg three times a day and one mg clonidine gel was applied to the same corresponding selected area on the left leg three times a day for a total administration of 6 mg clonidine/day for 14 consecutive days, during either Study Period (2) or Study Period (5).
- the gel was applied and rubbed into the skin.
- the application site was allowed to dry to the touch following application of the gel before clothing was allowed to contact the treated skin.
- the actual amount of gel applied for a total dose of 3 mg clonidine/day was found to be a mean value of about 3.1 mg/day and for a total of 6 mg clonidine/day was found to be a mean value of about 6.2 mg/day.
- FIG. 1 The systemic plasma concentrations seen with topical applications of 3 mg and 6 mg of clonidine per day are shown in FIG. 1.
- the data summarized in FIG. 1 shows a maximum mean plasma concentration of about 0.2 nanograms/ml at the 6 mg/day dose and about 0.05 nanograms/ml at the 3 mg/day dose. These plasma concentrations are at the bottom or below the range considered as the antihypertensive therapeutic threshold of 0.2 or 0.3 nanograms/ml. No side effects were observed in the eight volunteers who applied the 0.1% formulation at doses of either 3 mg or 6 mg per day for 14 consecutive days.
- Study A Patients suffering with sympathetically maintained neuropathic pain were selected for two clinical trials, Study A and Study B, conducted to determine the therapeutic effectiveness of a clonidine gel containing 0.1 weight percent clonidine hydrochloride.
- Study B systemic clonidine blood concentration from topical administration was also determined.
- Study A nine patients were selected who were affected with bilateral lower extremity, painful diabetic neuropathy.
- Study B nine patients were selected who were affected with postherpetic neuralgia on generally irregular bodily areas of the trunk.
- NGPS Numeric Graphic Pain Score
- a baseline NGPS value was assessed before starting the trial, and both NGPS and pain relief scores were assessed on each week of the trial following topical application of the topical clonidine gel.
- Each dose treatment was a period of seven days.
- the clonidine gel was applied by the patient to the affected painful region of the patient's body and rubbed into the skin.
- Sufficient topical gel was applied to provide a predetermined unit dosage amount of clonidine and total milligram (mg) amount of clonidine dose/day.
- the amount of clonidine dose/day was increased weekly by increasing the number of applications per day as described in the following protocol.
- Week 1 Sufficient gel to provide a unit dosage amount of about 0.625 mg clonidine per foot was applied twice a day for a total daily dose of 2.5 mg clonidine.
- Week 2 Sufficient gel to provide a unit dosage amount of about 0.625 mg clonidine per foot was applied three times a day, at spaced intervals of about 8 hours, to provide a total daily dose of 3.75 mg clonidine.
- Week 3 Sufficient gel to provide a unit dosage amount of about 0.625 mg clonidine per foot was applied four times a day, at spaced intervals of about 6 hours, to provide a total daily dose of 5 mg clonidine.
- each unit dosage amount applied was 0.5 mg clonidine for a total daily dose of clonidine during week 1 of 1 mg; during week 2 of 1.5 mg; and during week 3 of 2 mg.
- Example 3 The clinical trial procedure of Example 3 (Study A) was repeated, except that ten patients were selected who were affected with bilateral lower extremity, painful diabetic neuropathy and the treatment period was increased to two weeks.
- the six week trial (Study C) was conducted employing the clonidine gel of Example 1 containing 0.05 weight percent clonidine hydrochloride. The patients applied sufficient topical gel to the affected region to provide a predetermined unit dosage amount of clonidine and the total mg amount of clonidine dose/day was increased every two weeks by changing the number of applications per day as described in the following protocol.
- Weeks 1 & 2 Sufficient gel to provide a unit dosage of about 0.31 mg clonidine per foot was applied twice a day to provide a total daily dose of 1.25 mg clonidine.
- Weeks 3 & 4 Sufficient gel to provide a unit dosage of about 0.31 mg clonidine per foot was applied three times a day at spaced intervals of about eight hours to provide a total daily dose of 1.875 mg clonidine.
- Weeks 5 & 6 Sufficient gel to provide a unit dosage of about 0.31 mg clonidine per foot was applied four times a day at spaced intervals of about six hours to provide a total dose of 2.5 mg clonidine.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
- Bending Of Plates, Rods, And Pipes (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
Abstract
Description
______________________________________ Ingredient Conc. (% w/w) ______________________________________ Clonidine HCl 0.01 to 0.5 Water-gelling agent 0.1 to 2 Preservative 0.1 to 2 Topical anaesthetic zero to 5 Skin-humectant zero to 5 pH adjusting agent q.s. to final pH 7.5 to 8.5 Purified Water USP to 100% q.s. ______________________________________
______________________________________ Gram Components % (w/w) Amount ______________________________________ Clonidine Hydrochloride USP 0.05 0.5 Benzyl Alcohol NF 1 10 Carbomer.sup.1 0.5 5 Sodium Hydroxide NF q.s. (10% in water) to pH 8 Purified Water USP q.s. q.s. to 100% to 1 Kg ______________________________________ .sup.1 Carbopol 980 NF, B. F. Goodrich Corporation
TABLE 1 ______________________________________ STUDY A Painful Diabetic Neuropathy OutCome Data (dosing in mg of clonidine/day) Clonidine 0.1% gel Pa- Base- Pain Pain Pain tient line NGPS NGPC NGPS Relief Relief Relief # NGPS 2.5 mg 3.75 mg 5 mg 2.5 mg 3.75 mg 5 mg ______________________________________ 1 10 6 3 2 2 1 2 2 10 5 5 8 1 0 2 3 8 1 0 0 2 2 2 4 5 3 7 5 1 -1 1 5 10 5 8 5 0 0 0 6 8 5 4 4 1 1 1 7 8 6 5 0 2 1 2 8 7 8 7 DC 0 1 DC 9 4 6 1 1 1 2 2 Aver- 7.8 4.1 4.4 3.1 1.1 0.8 i.5 age ______________________________________ NGPS (Numerio Graphic Pain Score) scores ranged from 0, "No Pain" to 10, "Pain as bad as it could be" Pain Relief scores ranged from -1, More pain 0, No change; 1 Some relief; 2 Moderate relief; and 3 Complete relief DC Discontinued
TABLE 2 ______________________________________ STUDY B Postherpetic Neuralgia Outcome Data (dosing in mg of clonidine/day) Clonidine 0.1% gel Pa- Base- Pain Pain Pain tient line NGPS NGPC NGPS Relief Relief Relief # NGPS 1 mg 1.5 mg 2 mg 1.0 mg 1.5 mg 2 mg ______________________________________ 1 4 2 1 1 2 2 2 2 7 7 7 6 0 1 1 3 8 5 3 3 0 1 1 4 3 2 2 2 1 1 1 5 3 3 3 4 0 0 1 6 7 7 5 4 0 1 2 7 3 2 2 2 1 1 2 8 7 4 5 10 1 1 1 9 6 6 4 3 1 1 1 Aver- 5.3 4.2 3.5 3.9 0.7 1.0 1.3 age ______________________________________ NGPS (Numerio Graphic Pain Score) scores ranged from 0, "No Pain" to 10, "Pain as bad as it could be" Pain Relief scores ranged from -1, More pain 0, No change; 1 Some relief; 2 Moderate relief; and 3 Complete relief DC Discontinued
TABLE 3 ______________________________________ STUDY C Painful Diabetic Neuropathy Outcome (dosing in mg of clonidine/day) Clonidine 0.05% gel Pain Pa- Base- NGPS Pain Relief Pain tient line NGPS 1.875 NGPS Relief 1.875 Relief # NGPS 1.25 mg mg 2.5 mg 1.25 mg mg 2.5 mg ______________________________________ 1 5 5 3 3 1 2 2 2 6 4 2 4 1 2 2 3 6.5 7 6 6 2 2 2 4 5 5 3 2 1 2 2 5 4 3.5 2 1 2 2 2 6 6 5 5.5 4.5 1 1 2 7 4 1.5 1 2 2 2 2 8 8 5 5 0 2 2 3 9 8 7 7 0 2 2 3 10 3 1 3 0 2 2 3 Aver- 5.5 4.4 3.75 2.2 1.6 1.9 2.3 age ______________________________________ NGPS (Numerio Graphic Pain Score) scores ranged from 0, "No Pain" to 10, "Pain as bad as it could be" Pain Relief scores ranged from -1, More pain 0, No change; 1 Some relief; 2 Moderate relief; and 3 Complete relief DC Discontinued
Claims (25)
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/427,367 US6147102A (en) | 1999-10-26 | 1999-10-26 | Clonidine preparations |
CNB001209450A CN1148186C (en) | 1999-10-26 | 2000-08-07 | Clonidine preparation |
ES00973624T ES2359787T3 (en) | 1999-10-26 | 2000-10-18 | CLONIDINE PREPARATIONS. |
PT00973624T PT1248613E (en) | 1999-10-26 | 2000-10-18 | Clonidine preparations |
EP00973624A EP1248613B1 (en) | 1999-10-26 | 2000-10-18 | Clonidine preparations |
DK00973624.0T DK1248613T3 (en) | 1999-10-26 | 2000-10-18 | Clonidine preparations |
JP2001532765A JP4901042B2 (en) | 1999-10-26 | 2000-10-18 | Clonidine preparation |
AU12119/01A AU1211901A (en) | 1999-10-26 | 2000-10-18 | Clonidine preparations |
DE60045691T DE60045691D1 (en) | 1999-10-26 | 2000-10-18 | CLONDINZUBEREITUNGEN |
PCT/US2000/028776 WO2001030345A1 (en) | 1999-10-26 | 2000-10-18 | Clonidine preparations |
AT00973624T ATE499935T1 (en) | 1999-10-26 | 2000-10-18 | CLONED PREPARATIONS |
US09/710,138 US6534048B1 (en) | 1999-10-26 | 2000-11-10 | Topical clonidine preparation |
HK03102665.7A HK1050484A1 (en) | 1999-10-26 | 2003-04-11 | Clonidine preparations |
CY20111100439T CY1111463T1 (en) | 1999-10-26 | 2011-05-06 | CLONIDINE PREPARATIONS |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/427,367 US6147102A (en) | 1999-10-26 | 1999-10-26 | Clonidine preparations |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/710,138 Continuation US6534048B1 (en) | 1999-10-26 | 2000-11-10 | Topical clonidine preparation |
Publications (1)
Publication Number | Publication Date |
---|---|
US6147102A true US6147102A (en) | 2000-11-14 |
Family
ID=23694569
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/427,367 Expired - Lifetime US6147102A (en) | 1999-10-26 | 1999-10-26 | Clonidine preparations |
US09/710,138 Expired - Lifetime US6534048B1 (en) | 1999-10-26 | 2000-11-10 | Topical clonidine preparation |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/710,138 Expired - Lifetime US6534048B1 (en) | 1999-10-26 | 2000-11-10 | Topical clonidine preparation |
Country Status (13)
Country | Link |
---|---|
US (2) | US6147102A (en) |
EP (1) | EP1248613B1 (en) |
JP (1) | JP4901042B2 (en) |
CN (1) | CN1148186C (en) |
AT (1) | ATE499935T1 (en) |
AU (1) | AU1211901A (en) |
CY (1) | CY1111463T1 (en) |
DE (1) | DE60045691D1 (en) |
DK (1) | DK1248613T3 (en) |
ES (1) | ES2359787T3 (en) |
HK (1) | HK1050484A1 (en) |
PT (1) | PT1248613E (en) |
WO (1) | WO2001030345A1 (en) |
Cited By (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6544927B2 (en) | 2001-04-28 | 2003-04-08 | University Of Florida | Use of α2-adrenergic receptor agonists and adrenergic inhibitors in reducing defoliation |
US20040101582A1 (en) * | 2002-11-25 | 2004-05-27 | Richard Wolicki | Treatment of neuropathy |
US20040202706A1 (en) * | 2003-02-07 | 2004-10-14 | John Koo | Methods of administering a dermatological agent to a subject |
US20040220262A1 (en) * | 1999-12-16 | 2004-11-04 | Tsung-Min Hsu | Transdermal and topical administration of drugs using basic permeation enhancers |
US20040224007A1 (en) * | 2003-05-09 | 2004-11-11 | Cephalon, Inc. | Dissolvable backing layer for use with a transmucosal delivery device |
US20050112183A1 (en) * | 2003-11-25 | 2005-05-26 | Galer Bradley S. | Compositions and methods for treating neuropathic sensory loss |
US20060147510A1 (en) * | 2001-10-25 | 2006-07-06 | Endo Pharmaceuticals, Inc. | Method for treating non-neuropathic pain |
WO2007056460A2 (en) * | 2005-11-08 | 2007-05-18 | Arcion Therapeutics, Inc. | Treatment of length dependent neuropathy |
US20070142385A1 (en) * | 2005-11-08 | 2007-06-21 | Arc1, Inc. | Treatment of length dependent neuropathy |
US20070277873A1 (en) * | 2006-06-02 | 2007-12-06 | Emcore Corporation | Metamorphic layers in multijunction solar cells |
US7306812B2 (en) | 2003-05-09 | 2007-12-11 | Cephalon, Inc. | Dissolvable backing layer for use with a transmucosal delivery device |
US20080102097A1 (en) * | 2006-10-31 | 2008-05-01 | Zanella John M | Device and method for treating osteolysis using a drug depot to deliver an anti-inflammatory agent |
US20090197849A1 (en) * | 1999-12-16 | 2009-08-06 | Tsung-Min Hsu | Transdermal and topical administration of drugs using basic permeation enhancers |
US20090263448A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Clonidine Formulation in a Polyorthoester Carrier |
US20090263321A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Compositions and Methods for Treating Post-Operative Pain Using Clonidine and Bupivacaine |
US20090263462A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Methods for Treating Conditions Such as Dystonia and Post-Stroke Spasticity with Clonidine |
US20090264489A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Method for Treating Acute Pain with a Formulated Drug Depot in Combination with a Liquid Formulation |
US20090264490A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Clonidine formulations in a biodegradable polymer carrier |
US20090263459A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Methods and compositions for treating intervertebral disc herniations |
US20090264477A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc., An Indiana Corporation | Beta adrenergic receptor agonists for treatment of pain and/or inflammation |
US20090263450A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of inflammatory diseases |
US20090263463A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of pain and/or inflammation |
US20090263461A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of degenerative disc disease |
US20090263460A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Medical devices and methods including polymers having biologically active agents therein |
US20090263454A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Alpha and beta adrenergic receptor agonists for treatment of pain and / or inflammation |
US20090263489A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Analgesic and anti-inflammatory compositions and methods for reducing, preventing or treating pain and inflammation |
US20090264491A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Methods and compositions for treating post-operative pain comprising clonidine |
US20090263441A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Drug depots having diffreent release profiles for reducing, preventing or treating pain and inflammation |
US20100098746A1 (en) * | 2008-10-20 | 2010-04-22 | Warsaw Orthopedic, Inc. | Compositions and methods for treating periodontal disease comprising clonidine, sulindac and/or fluocinolone |
US20100137369A1 (en) * | 2008-12-01 | 2010-06-03 | Medtronic, Inc. | Flowable pharmaceutical depot |
US20100228097A1 (en) * | 2009-03-04 | 2010-09-09 | Warsaw Orthopedic, Inc. | Methods and compositions to diagnose pain |
US20100239632A1 (en) * | 2009-03-23 | 2010-09-23 | Warsaw Orthopedic, Inc. | Drug depots for treatment of pain and inflammation in sinus and nasal cavities or cardiac tissue |
USRE41998E1 (en) | 1990-02-26 | 2010-12-14 | Arclon Therapeutics, Inc. | Compositions and methods of treatment of sympathetically maintained pain |
US20110014259A1 (en) * | 2009-07-17 | 2011-01-20 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for prevention or treatment of a hematoma, edema, and/or deep vein thrombosis |
US20110027340A1 (en) * | 2009-07-31 | 2011-02-03 | Warsaw Orthopedic, Inc. | Implantable drug depot for weight control |
US20110178177A1 (en) * | 2008-09-27 | 2011-07-21 | Taraxos Inc. | Topical formulations for treatment of neuropathy |
WO2012012319A1 (en) | 2010-07-19 | 2012-01-26 | 3M Innovative Properties Company | Hand tool with replaceable knife cartridge |
WO2012012333A1 (en) * | 2010-07-19 | 2012-01-26 | Arcion Therapeutics, Inc. | Topical treatment of neuropathic pain and methods of diagnosis |
WO2013001073A1 (en) * | 2011-06-29 | 2013-01-03 | Galderma Research & Development | A new stable anesthetic composition for reducing skin reactions |
US20130123320A1 (en) * | 2011-11-14 | 2013-05-16 | Alex Chervinsky | Topical composition for pain relief |
US9358223B2 (en) | 2009-10-26 | 2016-06-07 | Warsaw Orthopedic, Inc. | Formulation for preventing or reducing bleeding at a surgical site |
US9610243B2 (en) | 2008-04-18 | 2017-04-04 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
US11185532B2 (en) | 2019-05-01 | 2021-11-30 | Clexio Biosciences Ltd. | Methods of treating pruritus |
USRE48948E1 (en) | 2008-04-18 | 2022-03-01 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8410102B2 (en) | 2003-05-27 | 2013-04-02 | Galderma Laboratories Inc. | Methods and compositions for treating or preventing erythema |
US7439241B2 (en) | 2003-05-27 | 2008-10-21 | Galderma Laboratories, Inc. | Compounds, formulations, and methods for treating or preventing rosacea |
US20050020600A1 (en) | 2003-07-23 | 2005-01-27 | Scherer Warren J. | Methods of treating cutaneous flushing using selective alpha-2-adrenergic receptor agonists |
CN101190183B (en) * | 2006-11-29 | 2010-05-12 | 上海医药工业研究院 | Clonidine hydrochloride multi-vesicular liposome and preparation method thereof |
CN101536981B (en) * | 2008-03-19 | 2010-11-17 | 上海医药工业研究院 | Clonidine hydrochloride multivesicular liposome and preparation method thereof |
US20090263451A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Anti-Inflammatory and/or Analgesic Agents for Treatment of Myofascial Pain |
US20100202979A1 (en) * | 2008-08-01 | 2010-08-12 | Gerald Horn | Compositions and methods for treatment of pulmonary diseases and conditions |
US20100203165A1 (en) | 2008-08-01 | 2010-08-12 | Gerald Horn | Compositions and methods for treatment of disorders or conditions of the eye |
US8952011B2 (en) | 2008-08-01 | 2015-02-10 | Eye Therapies Llc | Compositions and methods for the treatment of nasal conditions |
US20110003823A1 (en) * | 2008-08-01 | 2011-01-06 | Alpha Synergy Development, Inc. | Compositions and methods for treatment of diseases and conditions associated with vasodilation and/or vascular leakage |
US20100197694A1 (en) * | 2008-08-01 | 2010-08-05 | Gerald Horn | Compositions and methods for treatment of diseases and conditions with increased vascular permeability |
DK2320911T3 (en) * | 2008-08-01 | 2014-11-03 | Eye Therapies Llc | VASO CONSTRUCTION PREPARATIONS AND PROCEDURES FOR USE THEREOF |
US8987270B2 (en) | 2009-07-27 | 2015-03-24 | Eye Therapies Llc | Formulations of selective alpha-2 agonists and methods of use thereof |
EP2329849B1 (en) | 2009-11-18 | 2015-04-29 | Galderma Research & Development | Combination of alpha-2 adrenergic receptor agonist and non-steroidal anti-inflammatory agent for treating or preventing an inflammatory skin disorder |
US8394800B2 (en) | 2009-11-19 | 2013-03-12 | Galderma Laboratories, L.P. | Method for treating psoriasis |
DK2552449T3 (en) | 2010-03-26 | 2017-06-19 | Galderma Res & Dev | COMPOSITIONS INCLUDING BRIMONIDINE FOR TREATMENT OF ERYTHEM |
US8916562B2 (en) | 2010-03-26 | 2014-12-23 | Galderma Research & Development Snc | Methods and compositions for safe and effective treatment of telangiectasia |
EP2558101A4 (en) * | 2010-04-15 | 2013-09-18 | Univ Mcgill | Topical treatments for pain |
US8053427B1 (en) | 2010-10-21 | 2011-11-08 | Galderma R&D SNC | Brimonidine gel composition |
AR083651A1 (en) | 2010-10-21 | 2013-03-13 | Galderma Sa | BRIMONIDINE COMPOSITIONS IN GEL AND METHODS OF USE |
BR112021010700A2 (en) * | 2019-02-20 | 2021-08-24 | Gregory Aharonian | Methods and compositions to improve the taste of cola diet soft drinks and other beverages |
WO2020222192A1 (en) | 2019-05-01 | 2020-11-05 | Clexio Biosciences Ltd. | Methods of treating pruritus |
GB202110420D0 (en) * | 2021-07-20 | 2021-09-01 | Rosemont Pharmaceuticals Ltd | Liquid pharmaceutical composition of clonidine |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5447947A (en) * | 1990-02-26 | 1995-09-05 | Arc 1 | Compositions and methods of treatment of sympathetically maintained pain |
US5605911A (en) * | 1995-01-31 | 1997-02-25 | Washington University | Use of alpha-2 adrenergic drugs to prevent adverse effects of NMDA receptor hypofunction (NRH) |
US5780049A (en) * | 1991-10-16 | 1998-07-14 | Richardson-Vicks Inc. | Enhanced skin penetration system for improved topical delivery of drugs |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4801586A (en) * | 1986-04-23 | 1989-01-31 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agents |
IE60941B1 (en) * | 1986-07-10 | 1994-09-07 | Elan Transdermal Ltd | Transdermal drug delivery device |
US4808414A (en) * | 1986-09-29 | 1989-02-28 | Nelson Research & Development Co. | Amide penetration enhancers for transdermal delivery of systemic agents |
EP0268218B1 (en) * | 1986-11-19 | 1992-05-06 | WHITBY RESEARCH, Inc. | Penetration enhancers for transdermal delivery of systemic agents |
US5462744A (en) * | 1989-12-01 | 1995-10-31 | Boehringer Ingelheim Kg | Transdermal system for the administration of pharmacological compounds under pH-controlled conditions |
US5070084A (en) * | 1990-02-26 | 1991-12-03 | Campbell James N | Treatment of sympathetically maintained pain |
EP0516026A1 (en) * | 1991-05-28 | 1992-12-02 | Takeda Chemical Industries, Ltd. | Hydrogel and method of producing same |
US6365178B1 (en) * | 1996-09-06 | 2002-04-02 | Watson Pharmaceuticals, Inc. | Method of making pressure sensitive adhesive matrix patches for transdermal drug delivery using hydrophilic salts of drugs and hydrophobic pressure sensitive adhesive dispersions |
-
1999
- 1999-10-26 US US09/427,367 patent/US6147102A/en not_active Expired - Lifetime
-
2000
- 2000-08-07 CN CNB001209450A patent/CN1148186C/en not_active Expired - Fee Related
- 2000-10-18 JP JP2001532765A patent/JP4901042B2/en not_active Expired - Fee Related
- 2000-10-18 EP EP00973624A patent/EP1248613B1/en not_active Expired - Lifetime
- 2000-10-18 PT PT00973624T patent/PT1248613E/en unknown
- 2000-10-18 AU AU12119/01A patent/AU1211901A/en not_active Abandoned
- 2000-10-18 ES ES00973624T patent/ES2359787T3/en not_active Expired - Lifetime
- 2000-10-18 AT AT00973624T patent/ATE499935T1/en active
- 2000-10-18 WO PCT/US2000/028776 patent/WO2001030345A1/en active Application Filing
- 2000-10-18 DK DK00973624.0T patent/DK1248613T3/en active
- 2000-10-18 DE DE60045691T patent/DE60045691D1/en not_active Expired - Lifetime
- 2000-11-10 US US09/710,138 patent/US6534048B1/en not_active Expired - Lifetime
-
2003
- 2003-04-11 HK HK03102665.7A patent/HK1050484A1/en not_active IP Right Cessation
-
2011
- 2011-05-06 CY CY20111100439T patent/CY1111463T1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5447947A (en) * | 1990-02-26 | 1995-09-05 | Arc 1 | Compositions and methods of treatment of sympathetically maintained pain |
US5780049A (en) * | 1991-10-16 | 1998-07-14 | Richardson-Vicks Inc. | Enhanced skin penetration system for improved topical delivery of drugs |
US5605911A (en) * | 1995-01-31 | 1997-02-25 | Washington University | Use of alpha-2 adrenergic drugs to prevent adverse effects of NMDA receptor hypofunction (NRH) |
Non-Patent Citations (22)
Title |
---|
Byas Smith et al., Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two stage enriched enrollment design, Pain , 60, 267 274 (1995) (abstract). * |
Byas-Smith et al., "Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage `enriched enrollment` design," Pain, 60, 267-274 (1995) (abstract). |
Davis et al., "Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain," Pain, 47, 309-317 (1991) (abstract). |
Davis et al., Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain, Pain , 47, 309 317 (1991) (abstract). * |
Eisenach et al., "Epidural clonidine analgesia for intractable cancer pain:phase I," Anesthesiology, 71, 647-552 (1989) (abstract). |
Eisenach et al., Epidural clonidine analgesia for intractable cancer pain:phase I, Anesthesiology , 71, 647 552 (1989) (abstract). * |
Epstein et al., "Topical clonidine for orofacial pain: a pilot study," J. Orofac. Pain, 11, 346-352 (1997) (abstract). |
Epstein et al., Topical clonidine for orofacial pain: a pilot study, J. Orofac. Pain , 11, 346 352 (1997) (abstract). * |
Glynn et al., "A double-blind comparison between epidural morphine and epidural clonidine in patients with chronic non-cancer pain," Pain, 34, 123-128 (1988) (abstract). |
Glynn et al., A double blind comparison between epidural morphine and epidural clonidine in patients with chronic non cancer pain, Pain , 34, 123 128 (1988) (abstract). * |
Langley et al., "Transdermal clonidine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy," Drugs, 35, 123-142 (1988) (abstract). |
Langley et al., Transdermal clonidine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy, Drugs , 35, 123 142 (1988) (abstract). * |
Max et al., "Association of pain relief with drug side effects in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen and placebo," Clin. Pharmacol. Ther., 43, 363-371 (1988) (abstract). |
Max et al., Association of pain relief with drug side effects in postherpetic neuralgia: a single dose study of clonidine, codeine, ibuprofen and placebo, Clin. Pharmacol. Ther. , 43, 363 371 (1988) (abstract). * |
Mendez et al., "Epidural clonidine analgesia after cesarean section," Anesthesiology, 73, 848-852 (1990) (abstract). |
Mendez et al., Epidural clonidine analgesia after cesarean section, Anesthesiology , 73, 848 852 (1990) (abstract). * |
Nakamura et al., "Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances", Eur. J. Pharmacol., 146, 223-228 (1988) (abstract). |
Nakamura et al., Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin like substances , Eur. J. Pharmacol. , 146, 223 228 (1988) (abstract). * |
Yaksh, T.L., "Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing", Pharmacol. Biochem. Behav., 22, 845-858 (1985) (abstract). |
Yaksh, T.L., Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing , Pharmacol. Biochem. Behav. , 22, 845 858 (1985) (abstract). * |
Zeigler et al., "Transdermal clonidine versus placebo in painful diabetic neuropathy," Pain, 48, 403-408 (1992) (abstract). |
Zeigler et al., Transdermal clonidine versus placebo in painful diabetic neuropathy, Pain , 48, 403 408 (1992) (abstract). * |
Cited By (92)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE41998E1 (en) | 1990-02-26 | 2010-12-14 | Arclon Therapeutics, Inc. | Compositions and methods of treatment of sympathetically maintained pain |
US20090317453A1 (en) * | 1999-12-16 | 2009-12-24 | Dermatrends, Inc. | Transdermal and topical administration of drugs using basic permeation enhancers |
US20090197849A1 (en) * | 1999-12-16 | 2009-08-06 | Tsung-Min Hsu | Transdermal and topical administration of drugs using basic permeation enhancers |
US20040220262A1 (en) * | 1999-12-16 | 2004-11-04 | Tsung-Min Hsu | Transdermal and topical administration of drugs using basic permeation enhancers |
US6544927B2 (en) | 2001-04-28 | 2003-04-08 | University Of Florida | Use of α2-adrenergic receptor agonists and adrenergic inhibitors in reducing defoliation |
US20060147510A1 (en) * | 2001-10-25 | 2006-07-06 | Endo Pharmaceuticals, Inc. | Method for treating non-neuropathic pain |
US7687080B2 (en) * | 2002-11-25 | 2010-03-30 | Taraxos Inc. | Treatment of neuropathy |
US20120270916A1 (en) * | 2002-11-25 | 2012-10-25 | Taraxos Inc. | Topical formulations for treating neuropathy |
US20100184817A1 (en) * | 2002-11-25 | 2010-07-22 | Taraxos Inc. | Methods of treating neuropathy |
US8137711B2 (en) | 2002-11-25 | 2012-03-20 | Taraxos Inc. | Methods of treating neuropathy |
US20040101582A1 (en) * | 2002-11-25 | 2004-05-27 | Richard Wolicki | Treatment of neuropathy |
US9023392B2 (en) | 2003-02-07 | 2015-05-05 | Teikoku Pharma Usa, Inc. | Methods of administering a dermatological agent to a subject |
US8449913B2 (en) | 2003-02-07 | 2013-05-28 | Teikoku Pharma Usa, Inc. | Methods of administering a dermatological agent to a subject |
US20040202706A1 (en) * | 2003-02-07 | 2004-10-14 | John Koo | Methods of administering a dermatological agent to a subject |
US7887842B2 (en) | 2003-02-07 | 2011-02-15 | Teikoku Pharma Usa, Inc. | Methods of administering a dermatological agent to a subject |
US20040224007A1 (en) * | 2003-05-09 | 2004-11-11 | Cephalon, Inc. | Dissolvable backing layer for use with a transmucosal delivery device |
US7306812B2 (en) | 2003-05-09 | 2007-12-11 | Cephalon, Inc. | Dissolvable backing layer for use with a transmucosal delivery device |
US7276246B2 (en) | 2003-05-09 | 2007-10-02 | Cephalon, Inc. | Dissolvable backing layer for use with a transmucosal delivery device |
US20050112183A1 (en) * | 2003-11-25 | 2005-05-26 | Galer Bradley S. | Compositions and methods for treating neuropathic sensory loss |
WO2007056460A2 (en) * | 2005-11-08 | 2007-05-18 | Arcion Therapeutics, Inc. | Treatment of length dependent neuropathy |
KR101389184B1 (en) * | 2005-11-08 | 2014-04-24 | 아리콘 테라퓨틱스 아이엔씨 | A dosage formulation for treatment of length dependent neuropathy |
EP2343068A3 (en) * | 2005-11-08 | 2012-06-13 | Arcion Therapeutics, Inc. | Treatment of length dependent neuropathy |
US8962668B2 (en) | 2005-11-08 | 2015-02-24 | Arcion Therapeutics, Inc. | Treatment of length dependent neuropathy |
AU2010214659B2 (en) * | 2005-11-08 | 2012-02-02 | Arcion Therapeutics, Inc. | Treatment of length dependent neuropathy |
US8026266B2 (en) | 2005-11-08 | 2011-09-27 | Arcion Therapeutics, Inc. | Treatment of length dependent neuropathy |
EP2343068A2 (en) | 2005-11-08 | 2011-07-13 | Arcion Therapeutics, Inc. | Treatment of length dependent neuropathy |
WO2007056460A3 (en) * | 2005-11-08 | 2007-08-23 | Arc1 Inc | Treatment of length dependent neuropathy |
AU2006311580B2 (en) * | 2005-11-08 | 2010-06-24 | Arcion Therapeutics, Inc. | Treatment of length dependent neuropathy |
US20070142385A1 (en) * | 2005-11-08 | 2007-06-21 | Arc1, Inc. | Treatment of length dependent neuropathy |
US20070277873A1 (en) * | 2006-06-02 | 2007-12-06 | Emcore Corporation | Metamorphic layers in multijunction solar cells |
US20080102097A1 (en) * | 2006-10-31 | 2008-05-01 | Zanella John M | Device and method for treating osteolysis using a drug depot to deliver an anti-inflammatory agent |
US8968767B2 (en) | 2008-04-18 | 2015-03-03 | Warsaw Orthopedic, Inc. | Drug depots having different release profiles for reducing, preventing or treating pain and inflammation |
US20090264489A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Method for Treating Acute Pain with a Formulated Drug Depot in Combination with a Liquid Formulation |
USRE48948E1 (en) | 2008-04-18 | 2022-03-01 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
US20090263441A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Drug depots having diffreent release profiles for reducing, preventing or treating pain and inflammation |
US20090264491A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Methods and compositions for treating post-operative pain comprising clonidine |
US9833548B2 (en) | 2008-04-18 | 2017-12-05 | Warsaw Orthopedic, Inc. | Methods and compositions for treating post-operative pain comprising clonidine |
US9775800B2 (en) | 2008-04-18 | 2017-10-03 | Warsaw Orthopedic, Inc. | Compositions and methods for treating post-operative pain using clonidine and bupivacaine |
US20090263489A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Analgesic and anti-inflammatory compositions and methods for reducing, preventing or treating pain and inflammation |
US9770438B2 (en) | 2008-04-18 | 2017-09-26 | Warsaw Orthopedic, Inc. | Clonidine formulation in a polyorthoester carrier |
US9763917B2 (en) | 2008-04-18 | 2017-09-19 | Warsaw Orthopedic, Inc. | Clonidine formulations in a biodegradable polymer carrier |
US20090263454A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Alpha and beta adrenergic receptor agonists for treatment of pain and / or inflammation |
US20090263460A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Medical devices and methods including polymers having biologically active agents therein |
US9610243B2 (en) | 2008-04-18 | 2017-04-04 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
US20090263461A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of degenerative disc disease |
US9585872B2 (en) | 2008-04-18 | 2017-03-07 | Warsaw Orthopedic, Inc. | Clonidine formulations in a biodegradable polymer carrier |
US9492461B2 (en) | 2008-04-18 | 2016-11-15 | Warsaw Orthopedic, Inc. | Methods and compositions for treating intervertebral disc herniations |
US20090263463A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of pain and/or inflammation |
US20090263450A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of inflammatory diseases |
US20090264477A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc., An Indiana Corporation | Beta adrenergic receptor agonists for treatment of pain and/or inflammation |
US9387197B2 (en) | 2008-04-18 | 2016-07-12 | Warsaw Orthopedic, Inc. | Methods for treating conditions such as dystonia and post-stroke spasticity with clonidine |
US20090263459A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Methods and compositions for treating intervertebral disc herniations |
US9351959B2 (en) | 2008-04-18 | 2016-05-31 | Warsaw Orthopedic, Inc. | Alpha adreneric receptor agonists for treatment of degenerative disc disease |
US9265733B2 (en) | 2008-04-18 | 2016-02-23 | Warsaw Orthopedic, Inc. | Drug depots having different release profiles for reducing, preventing or treating pain and inflammation |
US8420114B2 (en) | 2008-04-18 | 2013-04-16 | Warsaw Orthopedic, Inc. | Alpha and beta adrenergic receptor agonists for treatment of pain and / or inflammation |
US9211285B2 (en) | 2008-04-18 | 2015-12-15 | Warsaw Orthopedic, Inc. | Methods and compositions for treating post-operative pain comprising clonidine |
US20090264490A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Clonidine formulations in a biodegradable polymer carrier |
US8470360B2 (en) | 2008-04-18 | 2013-06-25 | Warsaw Orthopedic, Inc. | Drug depots having different release profiles for reducing, preventing or treating pain and inflammation |
US8557273B2 (en) | 2008-04-18 | 2013-10-15 | Medtronic, Inc. | Medical devices and methods including polymers having biologically active agents therein |
US9132119B2 (en) | 2008-04-18 | 2015-09-15 | Medtronic, Inc. | Clonidine formulation in a polyorthoester carrier |
US9132085B2 (en) | 2008-04-18 | 2015-09-15 | Warsaw Orthopedic, Inc. | Compositions and methods for treating post-operative pain using clonidine and bupivacaine |
US8629172B2 (en) | 2008-04-18 | 2014-01-14 | Warsaw Orthopedic, Inc. | Methods and compositions for treating post-operative pain comprising clonidine |
US9072727B2 (en) | 2008-04-18 | 2015-07-07 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of degenerative disc disease |
US8722079B2 (en) | 2008-04-18 | 2014-05-13 | Warsaw Orthopedic, Inc. | Methods for treating conditions such as dystonia and post-stroke spasticity with clonidine |
US20090263448A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Clonidine Formulation in a Polyorthoester Carrier |
US8889173B2 (en) | 2008-04-18 | 2014-11-18 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of pain and/or inflammation |
US8946277B2 (en) | 2008-04-18 | 2015-02-03 | Warsaw Orthopedic, Inc. | Clonidine formulations in a biodegradable polymer carrier |
US8956641B2 (en) | 2008-04-18 | 2015-02-17 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of inflammatory diseases |
US20090263462A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Methods for Treating Conditions Such as Dystonia and Post-Stroke Spasticity with Clonidine |
US20090263321A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Compositions and Methods for Treating Post-Operative Pain Using Clonidine and Bupivacaine |
US8999368B2 (en) | 2008-04-18 | 2015-04-07 | Warsaw Orthopedic, Inc. | Medical devices and methods including polymers having biologically active agents therein |
US8629184B2 (en) | 2008-09-27 | 2014-01-14 | TARAXOS, Inc. | Topical formulations for treatment of neuropathy |
US20110178177A1 (en) * | 2008-09-27 | 2011-07-21 | Taraxos Inc. | Topical formulations for treatment of neuropathy |
US20100098746A1 (en) * | 2008-10-20 | 2010-04-22 | Warsaw Orthopedic, Inc. | Compositions and methods for treating periodontal disease comprising clonidine, sulindac and/or fluocinolone |
US8822546B2 (en) | 2008-12-01 | 2014-09-02 | Medtronic, Inc. | Flowable pharmaceutical depot |
US20100137369A1 (en) * | 2008-12-01 | 2010-06-03 | Medtronic, Inc. | Flowable pharmaceutical depot |
US20100228097A1 (en) * | 2009-03-04 | 2010-09-09 | Warsaw Orthopedic, Inc. | Methods and compositions to diagnose pain |
US10653619B2 (en) | 2009-03-23 | 2020-05-19 | Medtronic, Inc. | Drug depots for treatment of pain and inflammation |
US20100239632A1 (en) * | 2009-03-23 | 2010-09-23 | Warsaw Orthopedic, Inc. | Drug depots for treatment of pain and inflammation in sinus and nasal cavities or cardiac tissue |
US20110014259A1 (en) * | 2009-07-17 | 2011-01-20 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for prevention or treatment of a hematoma, edema, and/or deep vein thrombosis |
US8617583B2 (en) | 2009-07-17 | 2013-12-31 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for prevention or treatment of a hematoma, edema, and/or deep vein thrombosis |
US20110027340A1 (en) * | 2009-07-31 | 2011-02-03 | Warsaw Orthopedic, Inc. | Implantable drug depot for weight control |
US8231891B2 (en) | 2009-07-31 | 2012-07-31 | Warsaw Orthopedic, Inc. | Implantable drug depot for weight control |
US9358223B2 (en) | 2009-10-26 | 2016-06-07 | Warsaw Orthopedic, Inc. | Formulation for preventing or reducing bleeding at a surgical site |
WO2012012333A1 (en) * | 2010-07-19 | 2012-01-26 | Arcion Therapeutics, Inc. | Topical treatment of neuropathic pain and methods of diagnosis |
WO2012012319A1 (en) | 2010-07-19 | 2012-01-26 | 3M Innovative Properties Company | Hand tool with replaceable knife cartridge |
WO2013001073A1 (en) * | 2011-06-29 | 2013-01-03 | Galderma Research & Development | A new stable anesthetic composition for reducing skin reactions |
FR2977493A1 (en) * | 2011-07-05 | 2013-01-11 | Galderma Res & Dev | NOVEL STABLE ANESTHETIC COMPOSITION FOR REDUCING SKIN REACTIONS |
US9012486B2 (en) * | 2011-11-14 | 2015-04-21 | Alex Chervinsky | Topical composition for pain relief |
US20130123320A1 (en) * | 2011-11-14 | 2013-05-16 | Alex Chervinsky | Topical composition for pain relief |
US11185532B2 (en) | 2019-05-01 | 2021-11-30 | Clexio Biosciences Ltd. | Methods of treating pruritus |
US11903928B2 (en) | 2019-05-01 | 2024-02-20 | Clexio Biosciences Ltd. | Methods of treating pruritus |
Also Published As
Publication number | Publication date |
---|---|
DE60045691D1 (en) | 2011-04-14 |
CY1111463T1 (en) | 2015-08-05 |
EP1248613A4 (en) | 2006-03-22 |
JP2003512427A (en) | 2003-04-02 |
JP4901042B2 (en) | 2012-03-21 |
ATE499935T1 (en) | 2011-03-15 |
DK1248613T3 (en) | 2011-05-16 |
EP1248613A1 (en) | 2002-10-16 |
WO2001030345A1 (en) | 2001-05-03 |
EP1248613B1 (en) | 2011-03-02 |
CN1302608A (en) | 2001-07-11 |
AU1211901A (en) | 2001-05-08 |
ES2359787T3 (en) | 2011-05-26 |
US6534048B1 (en) | 2003-03-18 |
PT1248613E (en) | 2011-05-05 |
HK1050484A1 (en) | 2003-06-27 |
CN1148186C (en) | 2004-05-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6147102A (en) | Clonidine preparations | |
US7687080B2 (en) | Treatment of neuropathy | |
US6572880B2 (en) | Methods and transdermal compositions for pain relief | |
US6479074B2 (en) | Methods and transdermal compositions for pain relief | |
US20020015713A1 (en) | Methods and transdermal compositions for pain relief | |
JPH04210914A (en) | Method for percutaneous delivery of ibuprofen using water-alcohol gel | |
EP0506658B1 (en) | Compositions and method for treating painful, inflammatory or allergic disorders | |
WO2000000120A1 (en) | Methods and transdermal compositions for pain relief | |
US9012480B2 (en) | Topical therapy for migraine | |
MXPA02010347A (en) | Composition. | |
US20040131665A1 (en) | Topical anesthetic formulation | |
US8563616B2 (en) | Desensitizing drug product | |
JP7264813B2 (en) | Phenytoin for topical action for use in the treatment of peripheral neuropathic pain | |
JP2024507266A (en) | Hydrogel compositions and their use in the prevention and/or treatment of radiation-induced skin damage | |
KR100347883B1 (en) | New pharmaceutical composition of gel preparation containing local anaesthetic agents | |
JPH02501303A (en) | Permeation enhancers for local administration of systemic drugs | |
EP0880965A1 (en) | Topical pharmaceutical formulations containing nimesulide |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: CURATEK PHARMACEUTICALS LIMITED PARTNERSHIP, ILLIN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BORGMAN, ROBERT J.;REEL/FRAME:010508/0909 Effective date: 19991129 |
|
AS | Assignment |
Owner name: CURATEK PHARMACEUTICALS HOLDING, INC., NEVADA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CURATEK PHARMACEUTICALS LIMITED PARTNERSHIP;REEL/FRAME:010633/0517 Effective date: 20000202 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
FPAY | Fee payment |
Year of fee payment: 4 |
|
AS | Assignment |
Owner name: ARC1, INC., MARYLAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CURATEK PHARMACEUTICALS HOLDING, INC.;REEL/FRAME:018442/0901 Effective date: 20060905 |
|
FPAY | Fee payment |
Year of fee payment: 8 |
|
AS | Assignment |
Owner name: ARCION THERAPEUTICS, INC., MARYLAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ARC1, INC.;REEL/FRAME:021147/0096 Effective date: 20080515 |
|
FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
FPAY | Fee payment |
Year of fee payment: 12 |